therapeutic system for the treatment of psoriasis

ABSTRACT

A therapeutic system for topically administering active substances for the treatment of skin diseases involving severe cell proliferation is characterized in that the active substance is a pharmaceutically acceptable derivate of vitamin D 3 , with the exception of such derivates as serve to regulate the calcium metabolism.

The present invention relates to a therapeutic system for administeringactive substances belonging to the group of vitamin D₃ derivatives whichare suitable for use in the treatment of skin diseases characterized byabnormal cell proliferation and/or disturbed cell differentiation.

A great number of people--in Germany alone there are presumed to be 2millions concerned--suffer from psoriasis of different degrees ofseverity. This makes psoriasis one of the most frequent skin diseases.The cause for this skin disease is a genetic change which influences theimmune defence of the organism. For this reason, no possibility of acure has been found to this day. However, there are methods of treatmentavailable which can give considerable relief.

These are, first of all, external applications involving the applicationof active substances that reduce the accelerated cellular proliferationwhich is accompanied by scale formation, e.g. preparations of coal tar,salicylic acid, dithranol, cortisone, fumaric acid derivatives. Afurther therapeutic method is that of photochemotherapy. Occlusivedressings also contribute to an improvement. In addition, in severecases of psoriasis, internally active preparations such asglucocorticoids, vitamin A derivatives, cytostatic agents (methotrexate)or immunotherapeutics (cyclosporin A) are being used.

All these methods, which have been dealt with in numerous publications,have disadvantages and side effects such as

1. nephrotoxicity

2. embryotoxicity

3. gastrointestinal side effects

4. rebound effects.

Some agents which are to be applied locally require an additionalcovering in order to prevent clothing from being soiled.

It has been known for some years that the naturally occurring vitamin D₃is also capable of influencing psoriasis: in cell cultures vitamin D₃inhibited cell proliferation and induced a well-differentiated formationof cells.

Where a dosage as required for achieving a significant effect was used,however, it turned out that vitamin D₃ interfered considerably with thecalcium metabolism, both in oral and in cutaneous application.Consequently, a therapeutic use in the treatment of psoriasis was notpossible. For this reason vitamin D₃ derivates were synthesized with theintent of preventing or at least considerably reducing the side effectscaused by vitamin D₃, i.e. hypercalcemia, bone absorption andhypercalciuria.

Vitamin D₃ derivatives which serve to regulate the calcium metabolism,such as calcitriol, can therefore not be used for the purposes of thepresent invention. The synthesis of new vitamin D₃ analogues has beenpublished in EP 0 227 826 and WO 89/10 351. The substance calcipotrioldescribed therein is now available for therapeutic use. ##STR1##

Graphic Formula of Calcipotriol

The use of active substances in therapeutic systems has not beendescribed in these patents.

Of the plurality of derivatives described the synthetic 1,24-dihydroxyderivative of vitamin D₃ (INN calcipotriol), in particular, proves to bejust as effective in the cell culture in inducing differentiation andinhibiting proliferation in keratinocyte cultures as the vitamin D₃itself, its negative influence on the calcium metabolism, however, onlyamounting to a hundredth of that of vitamin D₃.

The therapeutic efficacy of calcipotriol-containing products incomparison to the standard methods of treatment has been proved. Theactive substance is to be used twice daily and has turned out to be welltolerated, with the exception of occasional burning sensations anditching. However, the dosis and thus the area which can be treated islimited due to the fact that with higher dosage an influence on thecalcium metabolism is still possible: Thus a maximum of 15 grams per dayor a maximum of 100 grams per week of an ointment preparation containing50 micrograms of calcipotriol in 1 gramme of ointment is not to beexceeded.

It is the object of the present invention to provide an administrationform which increases the efficacy of the active substance, i.e. improvesthe dosis/effect relation, further reduces side effects or avoids themaltogether, and enables an application method which is acceptable to theuser.

This object is achieved in accordance with the invention in that for theapplication of calcipotriol or other pharmaceutically acceptable vitaminD₃ derivatives which do not serve to regulate the calcium metabolism, atherapeutic system is employed. A therapeutic system is adrug-containing device or administration form which releases one or moredrugs at a predetermined rate, continuously, over a defined period oftime, to a defined application site (quoted according to HEILMANN,"Therapeutische Systeme", Ferdinand-Enke-Verlag, Stuttgart 1984).

As a matter of course, the use of prodrugs is also possible.

The use of therapeutic systems in the administration of activesubstances belonging to the group of vitamin D₃ derivatives, means thatapplication intervals, especially in local application, can beprolonged, that the controlled active substance liberation preventsabsorption peaks with subsequent systemic effect, that the treatment oflarger areas of skin is made possible, and that the duration oftreatment, which has so far been limited, can be prolonged, even withinterruptions--a very important factor in view of the life-longnecessity for treatment.

Moreover, such a therapeutic system at the same time provides a usefulcovering of the treated skin areas, which covering may remain on theskin for up to several days depending on the composition thereof. Thetherapeutic system has the positive effect of occlusion, which is knownfrom the literature, and the patients' hygienic needs can be solvedsatisfactorily. Application is effected after cutting the systems to theshape and size of the skin areas concerned.

Preferred therapeutic systems within the scope of the invention are, forexample, those in plaster form; they may, in principle, be present as:

1. membrane-controlled systems

2. matrix-controlled systems.

An example for plasters with membrane control is DE-A 21 35 533. Theseplasters, in principle, consist of a backing layer, forming one of thesurfaces, a layer of adhesive which is permeable to the active substanceand forms the other surface, and finally a reservoir comprising theactive substance between the two layers forming the surfaces.

As an alternative, the active substance may also be contained in aplurality of microcapsules which are distributed within the permeablelayer of adhesive.

In any case, the active substance is continuously delivered from thereservoir or the microcapsules through a membrane into the activesubstance-permeable layer of adhesive, which is in contact with thepatient's skin. In the case of microcapsules, the capsule material mayalso serve as a membrane.

A plaster having matrix diffusion control is described, for example, inDE-PS 33 15 272. It consists of an impermeable backing layer, a polymermatrix reservoir attached thereto which has a special structure andcontains the active substance in a concentration exceeding thesaturation concentration, a layer of adhesive connected to the reservoirand being permeable to the active substance, and a protective layercovering the layer of adhesive and being removable for use. Where thereservoir matrix is itself pressure-sensitive adhesive, the additionallayer of adhesive can be dispensed with.

The dosage of calcipotriol or one of the other pharmacologicallyacceptable vitamin D₃ derivatives must be selected such that releaserates are achieved the therapeutic efficacy of which equals that ofointment application. It must be taken into account in this connectionthat the therapeutic system can also remain on the skin for severaldays, if appropriate.

Advantageously, these systems release between 0.05 and 5.0 micrograms ofthe vitamin D₃ derivative per cm² and 24 h.

The therapeuctic systems described are used for the preparation ofready-for-use medicaments. This requires the establishing of parameterssuch as selection of active substance, dosis, control of release andrelease rate, composition of the reservoir and, as the case may be,addition of auxiliary substances. Thus, adding permeation enhancers,e.g. DMSO or AZON© can be useful for increasing the absorption in lowerskin layers. For the same reason, a further principle may also beconsidered for improving the permeation of active substances, namely theuse of electric current (iontophoresis).

The active substances may be introduced into a therapeutic system indifferent form; they may also be present in microencapsulated form.Finally, it may be useful to combine a vitamin D₃ analogue or vitamin D₃derivate with other active substances--with the aim of increasingefficacy, but also with the aim of reducing the individual doses ifrequired. Combinations are possible, for example, with cortisone,alpha-tocopherol, acetylsalicylic acid and/or fumaric acid.Advantageously, the therapeutic system comprises an activesubstance-containing reservoir on the basis of a gel layer or colloidlayer, for example in the form of a polyacrylate hydrogel or ahydrocolloid of gelatin, pectin or carboxymethyl cellulose.

Summarizing, the following advantages can be achieved with theabove-described therapeutic system which contains as active substance apharmaceutically acceptable derivative or analogue of vitamin D₃ in thetreatment of skin deseases involving abnormal cell proliferation and/ordisturbed cell differentiation:

controlled, constant active substance release along with the avoidanceof systemic availability,

improved dosis/effect-relation, avoidance of the limitations with regardto the duration of treatment and the extent of the skin areas treatedwhich apply to common, topic application

optimized treatment also with regard to therapeutic systems having aprotective function at the same time, improved acceptance with the user.

I claim:
 1. A therapeutic system for the administration of activesubstances in the treatment of skin diseases involving abnormal cellproliferation, said system being in the form of a plaster and comprisinga backing layer, an active substance reservoir connected thereto andmade up of a polymer matrix, and, where no other control mechanisms arepresent, a membrane controlling the active substance release, pressuresensitive adhesive means for affixing the system to the skin and,optionally, a protective layer which is removable prior to application,and said system containing calcipotriol of the formula ##STR2## asactive substance.
 2. A therapeutic system according to claim 1, whereinthe active substance is present as a prodrug.
 3. A therapeutic systemaccording to claim 1, wherein the system releases between 0.05 to 5.0micrograms of the calcipotriol per cm² per 24 hours.
 4. A therapeuticsystem according to claim 1 comprising a highly flexible, watervapour-permeable polymer film or sheet as backing layer.
 5. Atherapeutic system according to claim 4, wherein the polymer is apolyurethane.
 6. A therapeutic system according to claim 1, wherein theactive substance reservoir is formed with the aid of a gel layer orcolloid layer.
 7. A therapeutic system according to claim 1, wherein thediffusion of the active substance from the reservoir, or the permeationof the active substance into the skin is influenced by the addition ofsuitable substances.
 8. A therapeutic system according to claim 1,wherein a combination of the calcipotriol with other active substance isused.
 9. A therapeutic system according to claim 8, wherein the otheractive substance is at least one member selected from the groupconsisting of cortisone, alpha-tocopherol, acetylsalicylic acid andfumaric acid.
 10. A process for the production of a therapeutic systemaccording to claim 1, wherein calcipotriol is introduced into theadministration system in solid form, in solution or in dispersion,optionally with the addition of auxiliary agents.
 11. A method for thetreatment of skin diseases involving abnormal cell proliferation whichcomprises applying to the skin of a patient suffering from such diseasea therapeutic system as defined in claim 1.